Abstract Overall, Center for Chronic Pain and Drug Abuse: This is a resubmission of a P50 application, PAR-16-009, to launch a Center for Chronic Pain and Drug Abuse. Our Center proposal is built on the recognition that opioid addiction and chronic pain engage the same brain circuitry, the mesolimbic system. Although opiates continue to be prescribed to millions of chronic pain patients, and chronic pain is a primary contributor to the ongoing opiate epidemic, there is virtually no scientific knowledge regarding mechanisms that control the interaction between chronic pain and opioid exposure. Our Center is organized to uncover mechanisms that causally control this interaction, and to aggressively search for critical molecules, circuits, and biomarkers, and ultimately, novel non-addictive treatment options for chronic pain. Our overarching hypothesis is that the chronic pain state primes limbic circuitry for opiate abuse, and also, that associated adaptations depend on the duration and dose of both chronic pain and opioid exposure. The hypothesis will be rigorously tested using an array of cutting-edge tools, to study the underlying mechanisms from the scale of genes to molecules, circuits and whole-brain anatomy and function. Patients with chronic back pain (CBP) are the largest and best characterized group of humans at risk for opioid abuse disorder. Project 1 will use advanced brain imaging approaches to study brain properties in CBP, and in a rat model of chronic pain (SNI), for opioid exposure. The human studies will be 1) cross-sectional, comparing brain anatomy and function between groups; and 2) within-subject, examining brain activity and network properties during brief opioid withdrawal and re-exposure to placebo, opioid, or dopamine. The study seeks to identify: biomarkers for opioid use disorder (OUD); brain distortions and cognitive, emotional, and motor changes associated with opioid exposure; and the role of dopaminergic circuitry in OUD and opioid analgesia. Parallel brain imaging in rats with chronic pain (SNI) and with morphine exposure (MSA or MCPP) will establish cross-species correspondences, and interrogate circuitry studied in Projects 2-4. Project 2 will focus on circuits involved in motivation and addiction (mPFC, NAc, VTA); Project 3 will focus on episodic memory and relapse for opiate seeking (dorsal hippocampus, dH, interaction with VTA and cortex); Project 4 will focus on genetically defined single-cell adaptations for the mesolimbic region underlying opioid reinforcement (VTA and its connectivity to NAc and dH), searching for novel molecular targets to control chronic pain. All animal studies will use the same model for chronic pain. Projects 2-4 use genetically modified mice; Projects 2, 3 use opto- and chemo- genetics, and electrophysiology; and Project 4 uses single cell transcriptomics. The rodent behavior core will generate SNI rodents with MSA or MCPP for all projects. The computational and statistics core will provide data processing support, and enable data sharing with the research community at large. The administrative core will oversee the organizational, and educational missions of the program, including the pilot projects element, which will fund small projects from junior scientists to accelerate the Center?s science. 1